Medical Marijuana (-Derived Products) for Cancer Patients

38 accc-cancer.org | May–June 2020 | OI BY MELODY CHANG, RPH, MBA, BCOP

annabis, also known as marijuana, or called a vast number of other slang terms like weed, herb, pot, grass, bud, ganja, and Mary Jane originated in Central Asia but is grown Each state has its own list of the Cworldwide today. use for medicinal purposes dates qualifying conditions for which it will back at least 5,000 years, with the earliest reported use being in China around 2700 BC for the relief of pain and cramps.1 allow patients to use medical marijuana. In the , cannabis is still a controlled substance These qualifying conditions are different and is classified as a Schedule I agent (a drug with a high potential for abuse and currently no accepted medical use). The U.S. Food in each state; however, in many states and Drug Administration (FDA) has not approved cannabis as a number of conditions are cancer a treatment for cancer or any other medical condition. By federal law, the possession of cannabis is illegal, except within approved related—chemotherapy-induced nausea research settings. However, a growing number of states, territories, and vomiting, anxiety, hepatitis C, and the District of Columbia have enacted laws that decriminalized the recreational and/or medicinal use of marijuana in that specific HIV/AIDS, cachexia (wasting syndrome), area. Cannabis is the fastest growing industry in the world. Accord- and inflammatory bowel disease. ing to Arcview’s market research, regulated marijuana sales in North America totaled $6.9 billion in 2016. Sales are projected to increase to $21.6 billion by the year 2021.2 Over the last few decades, there has been significant interest in the potential use of History and Overview marijuana for a variety of medical conditions. There are more Cannabis is a genus of the family Cannabaceae and has generally than 60 U.S. and international health organizations that support been recognized to contain three main species: sativa, indica, and granting patients immediate legal access to medicinal marijuana ruderalis. and are both prevalent under a physician’s supervision.3 in the United States and other parts of the world. Cannabis sativa This article is intended to provide a general introduction and has been employed for thousands of years, primarily as a source overview regarding some of the important aspects and contem- of a stem fiber (both the plant and the fiber, termedhemp ) and porary issues encountered when navigating the field of medical a resinous intoxicant (the plant and its drug preparations, com- marijuana. monly termed marijuana).4

OI | May–June 2020 | accc-cancer.org 39 Figure 1. A Timeline of Cannabis History in the United States Compassionate Use Marihuana Tax Investigational New Cannabis was Act imposed a U. S. Congress Drug program is introduced into levy of 100 per passed the Boggs established; cannabis Western medicine by ounce of and included is distributed to Surgeon W.B. for non- with patients on a 10 11 O’Shaughnessy. use.10 narcotic drugs. case-by-case basis.

1839 1851 193 1942 1951 190 198 1992

Cannabis was Cannabis was Controlled Distribution of included in the removed from the Substance Act cannabis through third edition of the 12th edition of the passes; marijuana the compassionate Pharmacopeia of Pharmacopeia of is classified as a use program is the United States.8 the United Schedule I drug.10 closed to new States.10 patients.11

Traditionally, Cannabis sativa plants are tall, reaching heights Pharmacopoeia of the United States (USP). Subsequent revisions of up to 20 feet, loosely branched, and have long, narrow leaves. of the Pharmacopoeia described in detail how to prepare extracts On the other hand, Cannabis indica plants are short and densely and tinctures of dried cannabis flowers to be used as an analgesic, branched and have wider leaves. hypnotic, and anticonvulsant.8 The cannabis plant produces a resin containing compounds Cannabis was included in marketed products sold in the United called . Cannabinoids, also known as phytocanna- States by Eli Lilly and Company and other pharmaceutical com- binoids, are chemicals in cannabis that cause drug-like effects in panies for the treatment of a variety of conditions and/or disorders, the body, including the central nervous system and the immune including insomnia, migraines, and rheumatism.9 system. To date, more than 100 different cannabinoids have been Growing concerns about cannabis in the early 1900s resulted identified. Among these, Δ9- (THC) has in it being outlawed in several states, and the U.S. Treasury received the most attention for being responsible for the intoxi- Department introduced the Marihuana Tax Act in 1937. This cated state (psychoactive) sought by recreational cannabis users. Act imposed a levy of $1.00 per ounce for the medicinal use of Another active cannabinoid is (CBD), which may cannabis and $100 per ounce for non-medical use.10 In 1942, the relieve pain and lower inflammation without causing a “high” American Medical Association removed cannabis from the 12th from the THC.6 The highest concentration of cannabinoids is edition of the Pharmacopeia of the United States.10 In 1951, found in the female flowers of the plant. Congress passed the Boggs Act, which for the first time classified In general, marijuana refers only to the parts of the plant or cannabis with narcotic drugs.10 With the passage of the Controlled derivative products that contain substantial levels of THC. Under Substances Act in 1970, cannabis was classified by Congress as U.S. law, cannabis plants with very low levels of THC (no more a Schedule I drug. Drugs that are Schedule I are distinguished as than 0.3 percent) are not considered marijuana but instead are having no currently accepted medicinal use in the United States. industrial . Other Schedule I substances include heroin, lysergic acid dieth- Cannabis use for medicinal purposes dates back thousands of ylamide, mescaline, and methaqualone.10 Despite its designation years ago. It was introduced into Western medicine in 1839 by as having no medicinal use, cannabis was distributed by the U.S. W.B. O’Shaughnessy, a surgeon who learned of its medicinal government to patients on a case-by-case basis under the Com- properties while working in India for the British East India Com- passionate Use Investigational New Drug program established pany. Its use was credited with reported analgesic, sedative, in 1978. Distribution of cannabis through this program was anti-inflammatory, antispasmodic, and anticonvulsant effects.7 closed to new patients in 1992.11 Figure 1, above, shows a timeline In 1851, cannabis was included in the third edition of the of cannabis’s history in the United States.

40 accc-cancer.org | May–June 2020 | OI Legal Status: Federal and State Laws is a fee for applications, and each state has different limits on the Although federal law prohibits the use of cannabis, some states amounts patients are permitted to purchase. In most cases, the have enacted laws that legalized the recreational and/or medicinal purchasing cost of medical marijuana or medical CBD is not use of marijuana in that specific state.6 In 1996, California voters covered by insurance. passed Proposition 215, making California the first state in the To become a certified marijuana physician, a physician must United States to permit the use of medical marijuana.12 Colorado hold an active license, take a required course, and pass an exam. and Washington became the first two states to legalize the recre- This process varies by state. After completion of the state require- ational use of cannabis in 2012. ments, physicians may apply for certification.

States with Medical and Recreational Marijuana Laws Dispensing of Medical Marijuana or CBD Thirty-three states and the District of Columbia have passed As of November 30, 2019, 33 states, the District of Columbia, legislation legalizing marijuana for medical use. Of those, five Guam, Puerto Rico, and the U.S. Virgin Islands have passed have established a role for pharmacists in the dispensing medical marijuana laws (see Figure 2, page 42).13 Among them, process:14 10 states, the District of Columbia, and Guam also have legalized • Arkansas requires every marijuana dispensary to appoint a marijuana for recreational use. Those 10 states are Alaska, pharmacist consultant. California, Colorado, Maine, Massachusetts, Colorado, Nevada, • Connecticut permits only pharmacists to apply for and obtain Oregon, Vermont, and Washington.13 a marijuana dispensary license. States with Medical Cannabidiol (CBD) Laws • Minnesota permits only pharmacists to give final approval There are an additional 14 states—Alabama, Georgia, Indiana, for the distribution of medical marijuana to a patient. Iowa, Kansas, Kentucky, Mississippi, North Carolina, • New York requires a pharmacist to be on the premises and South Carolina, Tennessee, Texas, , Wyoming, and supervise the activities within a marijuana dispensing facility Wisconsin—where the use of medical marijuana has not been whenever the facility is open or in operation. legalized but a medical CBD law allowing for the use of cannabis • Pennsylvania requires primary marijuana dispensing facilities to have a physician or pharmacist on site when the facility is extracts that are high in CBD but minimum in THC has been open to receive patients and caregivers. passed.13 This is only in instances where a patient with a state- qualifying condition is recommended CBD by his or her Under federal law, no individual, including pharmacists, can provider.13 legally dispense medical marijuana, even in states that have passed Individual state laws are all different. Under Florida’s medical medical marijuana legislation. Absent a change to federal law, CBD law, state-qualified patients (patients with cancer or expe- pharmacists involved in the current dispensing process may ask riencing muscle spasms or seizures) may possess cannabis strains themselves whether their license is at risk for dispensing a federally containing 10 percent or more of CBD and no more than 0.8 prohibited drug or, if the medical marijuana is seized, whether percent of THC.13 In Texas, the THC limit is set at no more than they will be prosecuted. Unfortunately, there are no answers at 0.5 percent and CBD no less than 10 percent in oil preparations.13 this point. Currently, there are only three states in the United States that do Cannabinoid-Derived Pharmaceutical Products not allow the use of any form of medical marijuana—Idaho, The FDA has approved four drugs that are based on natural Nebraska, and South Dakota.13 cannabinoids (see Table 1, page 43); one is currently under It is important to have an understanding of the laws in your investigation.7 state. Regardless of what state you live in, you should not buy or send cannabis through the mail because the drug is still federally Cannabinoid-Derived Non-Pharmaceutical Products illegal. The U.S. Post Office, a federal government agency, will Cannabis is a flowering plant. Once mature, the plant’s leaves confiscate the marijuana, and the sender may be arrested and and flowers are covered with trichomes, tiny glands of resinous prosecuted. oil containing cannabinoids and terpenes, which provide physical and psychoactive effects.15 Cannabis leaves and flowers are con- State Legislature Conditions for Medical Use sumed in several forms: dried flower buds or various types of Each state has its own list of the qualifying conditions for which concentrated, loose, or pressed resin extracted from the flowers it will allow patients to use medical marijuana. These qualifying or leaves through a variety of methods, including: conditions are different in each state; however, in many states a • is a powder made from trichomes removed from the number of conditions are cancer related—chemotherapy-induced leaves and flowers of cannabis plants that is used for nausea and vomiting, anxiety, hepatitis C, HIV/AIDS, cachexia smoking. (wasting syndrome), and inflammatory bowel disease. Other • is a paste-like substance, a collection of compressed conditions include glaucoma, Tourette’s syndrome, multiple or concentrated trichomes, that is used for smoking, ingestion sclerosis, Alzheimer’s disease, and chronic pain. by food, or inhalation with a vaporizer. To purchase and use either medical marijuana or medical CBD • is a mix of essential oils and resins extracted from in states where it is legal, patients are usually required to register mature cannabis foliage that is used for smoking or inhalation and apply for a card with the state’s Department of Health. There with a vaporizer.

OI | May–June 2020 | accc-cancer.org 41 Figure 2. U.S. States and Territories That Have Approved the Medical Use of Marijuana and CBD

• Cannabis edibles are usually ingested or eaten when added The effects of THC, the psychoactive effect, are delayed by to brownies, cookies, dressings, and other foods. They can 30 to 60 minutes after eating or drinking marijuana-infused also be brewed into a tea or other beverage. products compared to just seconds or minutes after inhaling • Cannabis oil is a cooking oil infused with cannabinoids usu- marijuana smoke or vapor.12,13 The effects from ingestion can last ally used to help create cannabis edibles. up to 10 hours for some people. One should not drive due to • Cannabis tincture is an extract of cannabinoids with ethanol impaired coordination that can lead to unsafe driving. alcohol for use in droplet amounts that are absorbed through When oral cannabis is ingested, there is a low (6 percent to the mucous membranes in the mouth. 20 percent) and variable oral bioavailability. Peak plasma con- • Sublingual spray is similar to the tincture (above) but is placed centrations of THC occur after 1 to 6 hours and remain elevated under the tongue for use. with a terminal half-life of 20 to 30 hours. Taken by mouth, • Cannabis topicals are topical creams, lotions, ointments, and Δ9-THC is initially metabolized in the liver to 11-OH-THC, a patches that have cannabis (THC or CBD) in it. potent psychoactive metabolite.16,17 Unlike most pharmaceutical products, cannabis products are not Inhaled cannabinoids are rapidly absorbed into the blood- standardized in composition, formulation, or dose. This means stream with a peak concentration in 2 to 10 minutes, declining that there is not yet a way to know exactly what and how much rapidly for a period of 30 minutes and with less generation of THC or CBD is in each pill or spray. It will usually take experi- the psychoactive 11-OH metabolite.16,17 mentation with product types and dosages to determine the right In some states where marijuana has been legalized, smokable dose for individuals and their purpose. Digesting cannabis (not products are excluded. In New York, the law permits qualified smoking or absorbing it) also metabolizes the cannabinoids patients to possess a 30-day supply of cannabis-infused, non- somewhat differently, which can produce different subjective smokable products, with only non-smokable preparations effects, depending on the individual. allowed.18

42 accc-cancer.org | May–June 2020 | OI Table 1. FDA Approved Cannabinoid-Derived Pharmaceutical Products

Substance Route of Administration Descriptions Indications

Synthetic compounds

For chemotherapy-induced nausea and vomiting (Marinol) Oral capsule Synthetic THC or to stimulate appetite in AIDS wasting syndrome

For chemotherapy-induced nausea and vomiting Dronabinol (Syndros) Oral solution Synthetic THC or to stimulate appetite in AIDS wasting syndrome

For chemotherapy-induced nausea and vomiting Nabilone (Cesamet) Oral capsule Synthetic THC or to stimulate appetite in AIDS wasting syndrome

Natural product-derived compound

Concentrated CBD oil For the treatment of seizures associated with Epidiolex Oral oil (98 percent CBD) from Lennox-Gastaut syndrome or Dravet syndrome Cannabis extract

Nabiximol (Sativex) Ethanol Cannabis FDA Fast Track extract of TCH:CBD (approved in the Symptomatic relief of multiple sclerosis and as an Oromucosal spray (in a 1:1 ratio). Extract United Kingdom, adjuvant analgesic for cancer pain from two Cannabis Canada, and other plant varieties countries)

Marijuana smoke irritates the lungs. Frequent marijuana of 400 medical oncologists. Main outcome measures included smokers can have many of the same problems as tobacco smokers, whether oncologists:21 such as a daily cough, mucus, more chest colds, and a higher risk • Reported discussing medical marijuana with patients of lung infection. Some of the cancer-causing chemicals in tobacco • Recommended medical marijuana clinically in the past year smoke are also in marijuana smoke. Marijuana smokers may • Felt sufficiently informed to make such recommendations. also inhale deeper and hold the smoke in their lungs longer. Therefore, marijuana smokers’ lungs may be exposed to more The survey also queried oncologists’ views on medical marijuana’s chemicals that can cause cancer. Lung tissue from regular mari- comparative effectiveness for several conditions (including its use juana users shows signs of pre-cancerous changes.19 However, as an adjunct to standard pain management strategies) and its several studies have failed to show that marijuana smokers have risks compared with prescription opioids. The overall response a higher risk of lung cancer. More studies about marijuana smoking rate was 63 percent. Of all participants who responded, more 20 and lung cancer are needed. than half (55 percent) practice in states where medical marijuana 21 Knowledge Gaps is legal. Key findings from the survey include: According to survey results published in the Journal of Clinical • Eighty percent of oncologists conducted discussions about Oncology in 2018 titled “Medical Oncologists’ Beliefs, Practices, medical marijuana with their patients; 78 percent reported and Knowledge Regarding Marijuana Used Therapeutically: A that these conversations were most frequently initiated by Nationally Representative Survey Study,”21 Ilana M. Braun and patients and their families. colleagues concluded that a significant percentage of oncologists • Forty-six percent of oncologists recommended medical mar- who recommend medical marijuana to their patients did not feel ijuana clinically. knowledgeable enough to do so. This survey was mailed in • Seventy percent of oncologists did not feel sufficiently informed November 2016 to a nationally representative, random sample to make recommendations regarding medical marijuana.

OI | May–June 2020 | accc-cancer.org 43 • Sixty-seven percent viewed it as a helpful adjunct to standard 5. National Institute on Drug Abuse. What is medical marijuana? pain management strategies; a majority viewed it as presenting Available online at: drugabuse.gov/publications/drugfacts/marijuana- medicine. Revised July 2019. Last accessed February 15, 2020. a lower risk than opioids for overdose death (75 percent) and addiction (52 percent). 6. National Academies of Sciences, Engineering, and Medicine. The • Sixty-five percent thought that medical marijuana is equally Health and Cannabinoids: The Current State of Evidence and recommendations for Research. Washington, DC: The or more effective than standard treatments for anorexia and National Academies Press; 2017. cachexia. 7. Russo EB. History of cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers. 2007;4(8):1614-1648. 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